The conversion of T4 to T3, previously demonstrated in athyreotic human subjects has been investigated in normal subjects who were given intravenous injections of purified thyroxine labeled with carbon-14 in ring A and in the alanine side chain. Evidence for the conversion of T4 was provided by the findings of carbon-14 in the T3 fraction isolated from sera. It is estimated that an appreciable fraction of T4 may be transformed to T3 in normal man. Further studies have been undertaken regarding the metabolic significance of T3. Additional evidence of the extrathyroidal conversion of T4 to T3 has been obtained. This conversion has seemed to be appreciable in health and in most diseased conditions studied including thyroid disease, but appears somewhat impaired in advanced Laennec's cirrhosis. In addition, preliminary studies with cell cultures in vitro have also signified conversion of T4 to T3. The factor of artifactual conversion of T4 to T3 in analytic systems have been under scrutiny as a limitation on the accuracy of the foregoing studies. Current investigation has been devoted to studies of intracellular binding proteins including protein from the nucleus and mitochondria as well as the cytosol. Preliminary observations regarding cytosol binding protein obtained from perfused rat kidneys and livers have already been published. Preliminary gel filtration on Sephadex G-200 suggested a molecular weight approximating 70,000 daltons and physical chemical studies in progress suggest an association constant of 10 to the 9th power L/M, in other words, a low affinity, high capacity receptor protein in the cytosol. Since the number of binding sites per cell may well be numbered in the millions, this protein may well have a transport function rather than being a specific receptor which is translocated to the nucleus as in the case of the steroid hormones. Initial investigations have suggested binding proteins of even higher affinity in the nucleus and mitochondria.